UV RADIATION, DNA DAMAGE, MUTATIONS AND SKIN CANCER - Environmental UV Radiation: Impact on Ecosystems and Human Health and Predictive Models - page 242

In DNA the pyrimidines are more sensitive than purines (quantum yield about 10
times greater). The dominant DNA damage caused by UVC and UVB exposures is
targeted at neighbouring pyrimidines that become dimerized; either through a four-
carbon cyclobutane ring at the 5 and 6 positions in the successive bases or a binding of
the 6th position to the 4th in the next base, where the former adduct (the cyclobutane
pyrimidine dimer, CPD) is formed more frequently than the latter (the 6-4 pyrimidine-
pyrimidone photoproduct, 6-4PP). CPD distort the DNA helix less than 6-4PP.
Other DNA lesions are known to be caused by UV radiation, e.g., protein-DNA
crosslinks, oxidative base damage (e.g. 8-oxo-7,8-dihydroxyguanine, 8-oxo-G for short)
and single strand breaks. Especially, in the longwave UVA spectral region
(340 - 400 nm) these lesions become relatively more important 5 . There the DNA
absorption becomes vanishingly small, but the DNA can still be damaged by radicals
generated through absorption of the radiation by other (unidentified) molecules
("endogenous sensitizers", possibly riboflavins or porphyrins) in the cell. Reactive
oxygen species are known to play an important role in cellular damage by UVA
exposure (evidenced by oxygen dependency), which includes lipid peroxidation
(membrane damage) and oxidation of single bases in the DNA (for an overview see De
Laat and De Gruijl 6 ).
DNA repair and UVB vs UVA mutations
Pyrimidine dimers are the predominant DNA lesions caused by solar UV
radiation (the effect of UVB), and they are mainly repaired enzymatically by Nucleotide
Excision Repair (NER). Xeroderma pigmentosum (XP) patients lack this form of repair,
and run a dramatically increased risk of skin cancer 7 . This indicates that NER is a main
line of defence against UV carcinogenesis, which has been experimentally verified in
transgenic animals with deficiencies in NER 8-9 . The increased risk in patients with
XP-variant shows that besides NER, an other form of DNA repair is important. The
XP-variant patients are proficient in NER but lack functional DNA polymerase-K 10 .
This is a “sloppy” polymerase which can bypass a (UV-)damaged base, frequently
inserting an adenine. When mutated, the dysfunctional polymerase causes replication
problems and an increase in sister chromatide exchange by recombinational repair 11 .
The importance of recombinational repair of UV-induced DNA damage in human skin
remains to be determined, but it may obviously cause a different class of genetic
alterations from point mutations caused by pyrimidine dimers.
Fully in line with the predominance of pyrimidine dimers it was found that UVB
radiation induced point mutations almost exclusively at di-pyrimidine sites, with mostly
C to T transitions 12 (note that with random point mutations 75% would be expected to
be associated with di-pyrimidic sites). Despite the frequent dimer formation at these
sites, adjacent thymines did not appear to be associated with mutations; possibly by
default insertion of an adenine in the synthesized DNA strand opposite a
“non-instructive” (i.e., damaged) base in the template strand; a typical action of
polymerase-K, see above (the “A-rule” 13 ).
As mentioned earlier, UV radiation can generate reactive oxygen species (ROS)
which can cause oxidative damage to the DNA bases, e.g. forming 8-oxo-G. . 8-oxo-G is
a miscoding lesion causing G to T transversions 14 . Curiously enough, UVA irradiation